Is MYO7A p.Thr1841Met (c.5522C>T) pathogenic?

MYO7A p.Thr1841Met (c.5522C>T) is classified Uncertain significance in MYO7A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-23). AlphaMissense: ambiguous (0.4373); Ultra-rare (popmax 0.0122%, amr); Associated with autosomal recessive nonsyndromic hearing loss 2.

What condition is associated with MYO7A p.Thr1841Met (c.5522C>T)?

MYO7A p.Thr1841Met (c.5522C>T) is associated with autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, autosomal dominant nonsyndromic hearing loss 11 (ClinVar).

How common is MYO7A p.Thr1841Met (c.5522C>T) in the general population?

MYO7A p.Thr1841Met (c.5522C>T) is ultra-rare (popmax 0.0122%, amr) (gnomAD).

What do computational predictors say about MYO7A p.Thr1841Met (c.5522C>T)?

AlphaMissense predicts ambiguous (score 0.4373) — an in-silico prediction, not a clinical call.

MYO7A p.Thr1841Met

c.5522C>T · rs746667217 · VCV1387794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4373 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal recessive nonsyndromic hearing loss 2

Computational evidence

Protein change
AlphaMissense	0.4373	ambiguous
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -11.96	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0122% Admixed American · 7/57,600 alleles

Filtering AF 0.00564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00175% 28/1,596,326 alleles · ultra-rare exomes 24/1,444,138 · genomes 4/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0122%	8,229
Remaining individualsnot grpmax-eligible	0.00324%	30,903
African / African-American	0.00269%	37,208
East Asian	0.00228%	43,806
European (non-Finnish)	0.00136%	73,269

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MYO7A
Protein: p.Thr1841Met
Coding: c.5522C>T
MANE Select: NM_000260
dbSNP: rs746667217
Type: single nucleotide variant
Location: chr11:77205503 (GRCh38)
Gene constraint: LOEUF 0.995 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.73 · 1 PDB
Residue 1841: the myth4 2 domain; an α-helix

Full MYO7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal dominant nonsyndromic hearing loss 11

Similar variants

MYO7A p.Thr1841Ala Uncertain significance ★★ ⚠ same residue
MYO7A p.Thr1841= Likely benign ★ same residue
MYO7A p.Thr1841Arg Pathogenic/Likely pathogenic same residue
MYO7A p.Thr1841Ser Uncertain significance ⚠ same residue
MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-thr1841met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown